We show that MAPK inhibitor resistant melanoma cells exhibit low ATM expression increasing their sensitivity toward PARP inhibitors and that a combination of MAPK/PARP inhibitors act synthetically lethal in melanoma cells. To study the importance of ATM to PARPi treatment in melanoma on a functional level, we used the human melanoma cell line HT-144, that has the homozygous mutation p.W2845* in the ATM gene, resulting in a truncated and thereby inefficient ATM protein. Interestingly, the MUH analysis showed that the ATM-deficient cells are also sensitive to talazoparib treatment (Fig. 3G) and that inhibition of ATM by the ATM inhibitor Ku-55933 is more effective in A375 S cells than the corresponding R cells (Fig. 3H). Most strikingly, downregulation of ATM in A375 S cells via treatment with low concentrations of Ku-55933 sensitized the cells significantly to talazoparib treatment.